PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia

Mutations in the plant homeodomain-like finger protein 6 (PHF6) gene are strongly associated with acute myeloid (AML) and T-cell acute lymphoblastic leukemia (T-ALL). In this study, we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransf...

Descripción completa

Detalles Bibliográficos
Autores principales: Tsai, Hsiang-i, Wu, Yanping, Huang, Rui, Su, Dandan, Wu, Yingyi, Liu, Xiaoyan, Wang, Linglu, Xu, Zhanxue, Pang, Yuxin, Sun, Chong, He, Chao, Shu, Fan, Zhu, Haitao, Wang, Dongqing, Cheng, Fang, Huang, Laiqiang, Chen, Hongbo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279718/
https://www.ncbi.nlm.nih.gov/pubmed/35847518
http://dx.doi.org/10.1016/j.apsb.2021.10.025
_version_ 1784746461604347904
author Tsai, Hsiang-i
Wu, Yanping
Huang, Rui
Su, Dandan
Wu, Yingyi
Liu, Xiaoyan
Wang, Linglu
Xu, Zhanxue
Pang, Yuxin
Sun, Chong
He, Chao
Shu, Fan
Zhu, Haitao
Wang, Dongqing
Cheng, Fang
Huang, Laiqiang
Chen, Hongbo
author_facet Tsai, Hsiang-i
Wu, Yanping
Huang, Rui
Su, Dandan
Wu, Yingyi
Liu, Xiaoyan
Wang, Linglu
Xu, Zhanxue
Pang, Yuxin
Sun, Chong
He, Chao
Shu, Fan
Zhu, Haitao
Wang, Dongqing
Cheng, Fang
Huang, Laiqiang
Chen, Hongbo
author_sort Tsai, Hsiang-i
collection PubMed
description Mutations in the plant homeodomain-like finger protein 6 (PHF6) gene are strongly associated with acute myeloid (AML) and T-cell acute lymphoblastic leukemia (T-ALL). In this study, we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus. The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci, resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription. The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner, thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription. The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci, resulting in an increase in rDNA transcription activity, the proliferation of in vitro leukemia cells, and the growth of in vivo mouse xenografts. Importantly, significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6. The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine, the drug that is most commonly used to treat AML. Collectively, we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia.
format Online
Article
Text
id pubmed-9279718
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-92797182022-07-15 PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia Tsai, Hsiang-i Wu, Yanping Huang, Rui Su, Dandan Wu, Yingyi Liu, Xiaoyan Wang, Linglu Xu, Zhanxue Pang, Yuxin Sun, Chong He, Chao Shu, Fan Zhu, Haitao Wang, Dongqing Cheng, Fang Huang, Laiqiang Chen, Hongbo Acta Pharm Sin B Original Article Mutations in the plant homeodomain-like finger protein 6 (PHF6) gene are strongly associated with acute myeloid (AML) and T-cell acute lymphoblastic leukemia (T-ALL). In this study, we demonstrated that PHF6 can bind to H3K9me3 and H3K27me1 on the nucleolar chromatin and recruit histone methyltransferase SUV39H1 to the rDNA locus. The deletion of PHF6 caused a decrease in the recruitment of SUV39H1 to rDNA gene loci, resulting in a reduction in the level of H3K9me3 and the promotion of rDNA transcription. The knockdown of either SUV39H1 or PHF6 significantly attenuated the effects of increase in H3K9me3 and suppressed the transcription of rDNA induced by the overexpression of the other interacting partner, thereby establishing an interdependent relationship between PHF6 and SUV39H1 in their control of rRNA transcription. The PHF6 clinical mutants significantly impaired the ability to bind and recruit SUV39H1 to the rDNA loci, resulting in an increase in rDNA transcription activity, the proliferation of in vitro leukemia cells, and the growth of in vivo mouse xenografts. Importantly, significantly elevated levels of pre-rRNA were observed in clinical AML patients who possessed a mutated version of PHF6. The specific rDNA transcription inhibitor CX5461 significantly reduced the resistance of U937 AML cells deficient in PHF6 to cytarabine, the drug that is most commonly used to treat AML. Collectively, we revealed a novel molecular mechanism by which PHF6 recruits methyltransferase SUV39H1 to the nucleolar region in leukemia and provided a potential therapeutic target for PHF6-mutant leukemia. Elsevier 2022-04 2021-10-30 /pmc/articles/PMC9279718/ /pubmed/35847518 http://dx.doi.org/10.1016/j.apsb.2021.10.025 Text en © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Tsai, Hsiang-i
Wu, Yanping
Huang, Rui
Su, Dandan
Wu, Yingyi
Liu, Xiaoyan
Wang, Linglu
Xu, Zhanxue
Pang, Yuxin
Sun, Chong
He, Chao
Shu, Fan
Zhu, Haitao
Wang, Dongqing
Cheng, Fang
Huang, Laiqiang
Chen, Hongbo
PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia
title PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia
title_full PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia
title_fullStr PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia
title_full_unstemmed PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia
title_short PHF6 functions as a tumor suppressor by recruiting methyltransferase SUV39H1 to nucleolar region and offers a novel therapeutic target for PHF6-muntant leukemia
title_sort phf6 functions as a tumor suppressor by recruiting methyltransferase suv39h1 to nucleolar region and offers a novel therapeutic target for phf6-muntant leukemia
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279718/
https://www.ncbi.nlm.nih.gov/pubmed/35847518
http://dx.doi.org/10.1016/j.apsb.2021.10.025
work_keys_str_mv AT tsaihsiangi phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT wuyanping phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT huangrui phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT sudandan phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT wuyingyi phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT liuxiaoyan phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT wanglinglu phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT xuzhanxue phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT pangyuxin phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT sunchong phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT hechao phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT shufan phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT zhuhaitao phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT wangdongqing phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT chengfang phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT huanglaiqiang phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia
AT chenhongbo phf6functionsasatumorsuppressorbyrecruitingmethyltransferasesuv39h1tonucleolarregionandoffersanoveltherapeutictargetforphf6muntantleukemia